Chemogenetic attenuation of cortical seizures in nonhuman primates

Miyakawa, Naohisa; Nagai, Yuji; Hori, Yukiko; Mimura, Koki; Orihara, Asumi; Oyama, Kei; Matsuo, Tetsuji; Inoue, Kazuaki; Suzuki, Takafumi; Hirabayashi, Toshiyuki; Suhara, Tetsuya; Higuchi, Makoto; Kawasaki, Keisuke; Minamimoto, Takafumi

doi:10.1038/s41467-023-36642-6

Cited by 20 publications

(8 citation statements)

References 45 publications

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“…In the current study, we used AAV2.1 vectors with a human synapsin promoter (hSyn) for neuron-specific transduction of PSAM4-5HT3 with or without fusion protein tags. The combination of AAV2.1, hSyn, and HA/FLAG tags has been used in this study and in previous hM4Di/hM3Dq DREADD studies with macaque monkeys ( Kimura et al, 2023 ; Miyakawa et al, 2023 ). As expected, our AAV construct successfully induced PSAM4-5HT3 expression in the striatum and MI cortex, as visualized by [ 18 F]ASEM-PET.…”

Section: Discussionmentioning

confidence: 99%

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Multimodal Imaging for Validation and Optimization of Ion Channel-Based Chemogenetics in Nonhuman Primates

Hori,

Nagai,

Hori

et al. 2023

J. Neurosci.

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Chemogenetic tools provide an opportunity to manipulate neuronal activity and behavior selectively and repeatedly in nonhuman primates (NHPs) with minimal invasiveness. Designer Receptors Exclusively Activated by Designer Drugs are one example that is based on mutated muscarinic acetylcholine receptors. Another channel-based chemogenetic system available for neuronal modulation in NHPs uses Pharmacologically Selective Actuator Modules (PSAMs), which are selectively activated by Pharmacologically Selective Effector Molecules (PSEMs). To facilitate the use of the PSAM/PSEM system, the selection and dosage of PSEMs should be validated and optimized for NHPs. To this end, we used a multimodal imaging approach. We virally expressed excitatory PSAM (PSAM4-5HT3) in the striatum and the primary motor cortex of two male macaque monkeys, and visualized its location through positron emission tomography (PET) with the reporter ligand [18F]ASEM. Chemogenetic excitability of neurons triggered by two PSEMs (uPSEM817 and uPSEM792) was evaluated using [18F]fluorodeoxyglucose-PET imaging, with uPSEM817 being more efficient than uPSEM792. Pharmacological magnetic resonance imaging showed that increased brain activity in the PSAM4-expressing region began approximately 13 min after uPSEM817 administration and continued for at least 60 min. Our multimodal imaging data provide valuable information regarding the manipulation of neuronal activity using the PSAM/PSEM system in NHPs, facilitating future applications.Significance statementLike other chemogenetic tools, the ion channel-based system called Pharmacologically Selective Actuator Module/Pharmacologically Selective Effector Molecule (PSAM/PSEM) allows remote manipulation of neuronal activity and behavior in living animals. Nevertheless, its application in non-human primates (NHPs) is still limited. Here, we used multi-tracer positron emission tomography (PET) imaging and pharmacological magnetic resonance imaging (MRI) to visualize an excitatory chemogenetic ion channel (PSAM4-5HT3) and validate its chemometric function in macaque monkeys. Our results provide the optimal agonist, dose, and timing for chemogenetic neuronal manipulation, facilitating the use of the PSAM/PSEM system and expanding the flexibility and reliability of circuit manipulation in NHPs in a variety of situations.

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Section: Discussionmentioning

confidence: 99%

“…MI injections in MK#1 were performed under direct vision using the same type of surgical procedures as described previously ( Miyakawa et al, 2023 ). The putative hand/arm target region of the right MI was determined based on sulcal landmarks from a presurgical MRI.…”

Section: Methodsmentioning

confidence: 99%

Multimodal Imaging for Validation and Optimization of Ion Channel-Based Chemogenetics in Nonhuman Primates

Hori,

Nagai,

Hori

et al. 2023

J. Neurosci.

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“… 21 , 22 Recently, a decrease in cortical seizure severity using AAV-hM4D(Gi), coupled with systemic injection of deschloroclozapine, has been shown in NHPs. 23 …”

Section: Treating the Symptomsmentioning

confidence: 99%

Are Genetic Therapies for Epilepsy Ready for the Clinic?

2023

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In recent years, there has been a significant increase in preclinical studies to test genetic therapies for epilepsy. Some of these therapies have advanced to clinical trials and are being tested in patients with monogenetic or focal refractory epilepsy. This article provides an overview of the current state of preclinical studies that show potential for clinical translation. Specifically, we focus on genetic therapies that have demonstrated a clear effect on seizures in animal models and have the potential to be translated to clinical settings. Both therapies targeting the cause of the disease and those that treat symptoms are discussed. We believe that the next few years will be crucial in determining the potential of genetic therapies for treating patients with epilepsy.

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“…deschloroclozapine, DCZ), the optimization of the generally applied Adeno-Associated Virus (AAV) gene transfer method (virus dose-, titer-, promoter-and serotype selection), the proper toxicological evaluation in the nervous tissue, and the validation of appropriate proof of concept (POC) and " rst in vivo" methods to measure in vivo effectiveness quickly and reliably in rodent behavioral paradigms. Although the generation of in vivo chemogenetic POC studies has been started (e.g., in Parkinson's disease [9][10][11] or epilepsy [12][13][14]), the human translational validity of these pioneering studies is debatable, because of the above detailed methodological aws. Moreover, several high unmet need CNS indications would be potentially suitable targets for chemogenetic drug discovery [2], and more that are completely lacking the proper preclinical in vivo POC studies, including obesity, as a potential future target indication for chemogenetic therapies.…”

Section: Introductionmentioning

confidence: 99%

Chemogenetic inhibition of the lateral hypothalamus in rats: A simple but robust tool with high translational relevance to facilitate the development of central nervous system-targeted gene therapies

Kovács,

Kitka,

Bali

et al. 2023

Preprint

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Aims Despite the therapeutic potential of chemogenetics, the method lacks comprehensive preclinical validation, hindering its progression to human clinical trials. We aimed to validate a robust but simple in vivo assay in rats, which could support chemogenetic drug discovery. We also aimed to establish the proof-of-concept for the chemogenetic approach in obesity indication. Methods Key methodological parameters such as adeno-associated virus (AAV) serotype, actuator drug, dose, and application routes were investigated by measuring the food-intake-reducing effect of chemogenetic inhibition of the lateral hypothalamus (LH) by hM4D(Gi) designer receptor stimulation. Results Subcutaneous deschloroclozapine in rats transfected with AAV9 resulted in a substantial reduction of food-intake, comparable to the efficacy of exenatide. We estimated that the effect of deschloroclozapine lasts for 1–3 hours post-administration. AAV5, oral administration of deschloroclozapine, and clozapine-n-oxide were also effective but with slightly less potency. The strongest effect on food-intake occurred within the first 30 min after re-feeding, suggesting this as the optimal experimental endpoint. Conclusion This study demonstrates that the chemogenetic silencing of the LH is a potential strategy in obesity treatment. The study also supports the development of chemogenetics by providing a “first in vivo” tool for the validation of new chemogenetic constructs.

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Chemogenetic attenuation of cortical seizures in nonhuman primates

Cited by 20 publications

References 45 publications

Multimodal Imaging for Validation and Optimization of Ion Channel-Based Chemogenetics in Nonhuman Primates

Multimodal Imaging for Validation and Optimization of Ion Channel-Based Chemogenetics in Nonhuman Primates

Are Genetic Therapies for Epilepsy Ready for the Clinic?

Chemogenetic inhibition of the lateral hypothalamus in rats: A simple but robust tool with high translational relevance to facilitate the development of central nervous system-targeted gene therapies

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